,130 Journal of Medicinal Chemistv, 1975, Vol. 18, No. 4
Notes
(2) R. E. McMahon, J. Pharrn. Sci., 55,457 (1966). ( 3 ) C. Elison, H. W. Elliot, M. Look, and H. Rapoport, J . Med.
Chem., 6,237 (1963). (4) E. Kutter, A. Herz, H. Teschemacher, and R. Hess, J . Med. (‘hem., 13,801 (1970).
(5) C. Mitoma, D.M. Yasuda, J. Tagg, and M. Tanabe, Biochem. Biophys. Acta, 136,566 (1967). (6) E. H. Woudruff, 3. P. Lamboog, and W. E. Burt, J iimer. Chem. Soc., 62,922(1940). (7) F. H. Westheimer, Chem. Reu., 61,265 (1961).
Notes Antiparasitic Nitroimidazoles. 9. Synthesis of Some 2-( 4-Dialkylaminomethylstyryl)and 2-( 4-Amidinostyryl)-5-nitro- 1-vinylimidazoles William J. Ross* and William B. Jamieson L i l l y Research Centre, Ltd., Erl Wood Manor, Windlesham, Surrey, England Received Ju13 1, 1974
A series of 2-styryl-5-nitro-1-vinylimidazoles carrying alkylaminomethyl or amidino functions in the 4 position of the styryl ring was prepared and evaluated for antitrypanosomal activity in mice infected with Trypanosoma rhodesiense. The alkylaminomethyl compounds were found inactive against Trypanosoma cruzi infections in mice. One hydrochloride, showed antitrypanosomal activity compound, 2-(4-methylamidinostyryl)-5-nitro-l-vinylimidazole comparable to the standard drugs suramin, pentamidine, diminazene, and melarsoprol when tested ip against T . rhodesiense infected mice and also showed some activity when tested ip against T. cruzi infected mice.
In paper 3l we described the antitrypanosomal activity of la and various amides derived from it. These amides can be regarded as intermediates, the further elaboration of which may yield compounds with enhanced biological activity. Firstly, reduction of the amides would give rise to 4aminoalkylmethylstyrylnitroimidazoles lb in which the polar carboxyl group of la has been replaced by a strongly basic group, thus changing the character of the compounds. Secondly, the conversion of the amides to amidines IC would give tautomeric compounds which might be regarded as basic analogs of the acidic carboxyl group in la. The preparation of the amidines has the added attraction that the compounds may be considered as nitroimidazole analogs of 4,4’-diamidinostilbene (stilbamidine), a compound found to be active against a number of protozoal infectiom2 Although simple monoamidines are generally i n a ~ t i v eSexton4 ,~ has pointed out that in the diamidine series it is possible t o replace one amidine residue with another type of polar function and retain antiprotozoal activity. In our case, we would regard the nitro group as the second polar function.
Scheme I OEt
I
Fro’ BF-
R(QKR’R”
CH C1
f
RC=h’R’R’
BF,-
haBH, EtOH
RCHJR’R”
CH=CHI
the reduction of amides, uia the imino ethers, using sodium borohydride (Scheme I) and we applied this method successfully to a number of tertiary amides. We were able to prepare only one example of a secondary amine 2 (Table I) because the intermediate imino ethers were either too unstable to isolate or did not form readily. The amidines (Table 11) were prepared via the imino ether derived from the primary amidel Id using modifications of the methods described by Barber and Slack6 or D o x . ~(Scheme 11). The amidoxime 15 was prepared from the nitrile le.’ Scheme I1
CH=CH.
RCOKH?
la. R = COOH
b, R = -CH,NR,’ . -
”H
(Et1 0’ BF,.
/OEt
KC
,NHR‘ 1 liquid
%H
XH
hOH
i
R as in Scheme I
C.R=-C “R‘R” d. R = -CONHJ e . R = -CN
Chemistry. The presence of a nitro group and an olefinic function in our starting compounds prevented the use of conventional reducing agents such as lithium aluminium hydride or diborane for the preparation of the alkylaminornethyl compounds. However, Borch5 has recently described a procedure for
Biological Results. All the compounds in Table I11 were tested ip or PO against infections of T r y p a n o s o m a r h o d e s i e n s e and T r y p a n o s o m a cruzi in mice according to procedures described by Hawking? Apart from the secondary amine 2 none of the compounds approached the activity of l a against 2’. r h o d e s i e n s e and all were inactive against T. c r u z i a t doses of up to 200 mg/kg X 5 ip. I t thus appears that replacement of the carboxyl group of la by a basic function reduces antitrypanosomal activity. Compounds 10-15 (Table IV) were tested sc and po
Notes
Journal ofMedicinal Chemistry, 1975, Vol. 18, No. 4 431
Table I
O Compd
J
Yield, %
R
F
C
H
=
C- H
~
J
CH----CH, Crystn solvent
I
MP, "C
Formula'
258-260 dec 89-90 227-228 dec 128-1 29 63-64 133-134 99-100 225-227dec
C 1 8 Hi ,N402*HC1
~
6 48 50 58 45 12 20 21
NH Et N(Et)z N(Et)2 N (i -Pr )z N(n-Bu), c -N(CH,CH,),O c -N(cH,), c-N(C
2 3 4 5
6 7 8
9
EtOH-HC 1 EtOH EtOH-HC 1 EtOH EtOH EtOH EtOH EtOH-HC1
18H22N402
C 18H22N402.HCl C20H26N402 C22H30N402 1B H 2 0 N 4 0 3
1 8H20N402
Ci,H2oN,02*HCl
"All compounds were analyzed for C, H, and N .
Table 11
CH=CH
O*N
Compd
R"
R'
-
CH=CH2 Yield, % Crystn Solvent
%Rr' MP, "C
Formula'
~~~~
10 11 12 13 14 15
H
H
Me Et C - (C n-Bu H
H H H
50 11 69 70 40 66
H OH
EtOH Et0 H-HC 1 EtOH EtOH CHC13 DMF
188-190 279-280 190-191 199-200 143-144 249-250
dec dec dec dec dec dec
14H1 3N502
C ,,Hi,N502*HCl.O. 5H20 C16H17N502
C1TH17N502 18H21N502 C14Hi3N503
"All compounds were analyzed for C, H, and N.
Table 111.Minimum Dose Level in mg/kg 100% Effective against Trypanosomal Infections in Mice T.
Table IV. Minimum Dose Level in mg/kg 100% Effective against Trypanosomal Infections in Mice T . rhodesiense"
T. rhodesiense"
yhodesiense"
Compd
~
Compd
ip
PO
Compd
2 3 4 5 6 7 8
30 200 >50 200 200 100 100
30 200 >50 >200 200 200 >50
9 la Suramin Pentamidine Diminazene Melarsoprol
~~
~~
iP
PO
> 50
> 50
10 11
25 Inact Inact Inact 0.5
12 13 14 15 l a Na salt
25 1 1.25 1 0.75
~
"Mice were dosed for four consecutive days, commencing on the day of infection. 100% efficacy is equivalent to 30-day post-infection survival with negative parasitemia.
against T. rhodesiense infections in mice. The most active compound sc was 10 followed by 11. Lengthening of the alkyl chain to give the ethyl 12 and butyl 14 analogs of 11 reduced biological activity while introduction of a cyclopropyl group resulted in a barely active compound 13 a t comparable dose levels. The amidines, with the exception of 13, and the amidoxime 15 were much more active sc than the sodium salt of la. Compounds 11 and' 15 exhibited good oral activity against T.rhodesiense 10 mg/kg X 4 but none of the other amidines cured mice of the infection at this dose level. Nevertheless, compounds 10, 11, 14, and 15 compare favor-
sc
PO
1 2 3 >> 3 3 2 15
10 12 > 10 Inact at 10 > 10 10 50
aMice were dosed for four consecutive days, commencing on the day of infection. 100% efficacy is equivalent to 30-day post-infection survival with negative parasitemia. ably with la (Table IV). Only one compound, 11, was tested ip against T. rhodesiense in mice giving a parasitological cure a t 1 mg/kg X 4,a dose level comparable to the standard drugs suramin, pentamidine, diminazene, and melarsoprol (Table 111). In addition, compound 11 was tested against T.cruzi infections in mice and gave an 80% cure rate at 50 mg/kg X 5 ip. None of the other amidines were tested against this organism. In conclusion, we can say that replacement of the carboxyl group of la by a basic dialkyl aminomethyl function is deleterious to the antitrypanosomal activity of this class of compound whereas introduction of an amidino residue appears to enhance activity, particularly against T. rhodesiense.
432 Journal ojMedicinal ChemistT, 1975, Vol 18, h’o. 4
>Votes
x 200 ml) (some insoluble removed here) and the filtrate was made alkaline (4 N NaOH). After extraction into CHC13 and concentraMelting points were taken on a Gallenkamp apparatus (Registion, the product was obtained as yellow crystals: yield 1.4 g (400/0); tered Design No. 889339) using capillaries and are uncorrected. All mp 143-144O. Compounds 10,12, and 13 were similarly prepared. compounds were characterized by ir, uv, nmr, and elemental analy2-(4-N-Methylamidinostyryl)-5-nitro-l-vinylimidazole Hyses (C, H, N) which were within f0.446of the theoretical values. drochloride. The imino ether tetrafluoborate, 25 g (0.062 mol), Triethyloxonium fluoborate was prepared by the method of prepared as above, was stirred in EtOH (200ml) and treated with Meerweing and successfully stored under anhydrous Et20 for perimethylamine in EtOH (12 ml, 33% w/w solution). After stirring for ods up to 6 months. 3 days a t room temperature (closed flask), the resultant solid was 2-(4-N,N-Di-n-butylaminomethylstyryl)-5-nitrol-vinylifiltered off, dissolved in warm water, and made alkaline (4 1%’ midazole (6). 2-(4-N,N-Di-n-butylcarbamoylstyryl)-5-nitro-l- NaOH). The yellow solid which formed was purified twice uia the vinylimidazole, 18.2 g (0.046 mol), was stirred in CHzCl2 (100 ml) sequence: treatment with hot dilute HC1 solution. filtration, and a t room temperature. A solution of triethyloxonium fluoborate, 9.8 reprecipitation with 4 N NaOH and finally by crystallization from g (0.051 mol), in CHzClz (20 ml) was added rapidly and the clear EtOH-HCl to give the desired compound as the hydrochloride: orange yellow solution stirred for 20 hr. CHzClz was removed i n yield 2.2 g (11%);mp 279-280” dec. LWUO (rotary), the resultant viscous oil was stirred with EtOH 2-(4-Hydroxyamidinostyryl)-5-nitro-l-vinylimidazole(15). (100 ml) and cooled to Oo, and N a B h (4.5 g) added in small porA mixture of hydroxylamine hydrochloride, 2.45 g (0.035 mol). tions over 1 hr. After stirring at room temperature overnight, the MeOH (35 ml), and 5 N NaOH solution (7 ml) was added to the hazy solution was poured into H20 (300 ml) and the resultant yelcyano compound le, 9.3 g (0.035 mol), in EtOH (500 ml) and relow oily solid was separated, taken up in EtOH (50 ml), treated fluxed for 24 hr. The mixture, containing a lighter yellow solid with EtOH-HC1, and evaporated to dryness twice in the presence than a t the start, was filtered hot and the resulting solid washed of 2-propanol. The crystalline solid was treated with hot HzO (100 with H20 (to remove NaCl), then extracted with boiling CHC13 (to ml) (small precipitate removed here by filtration), the clear filtrate remove unreacted cyano compound), and finally crystallized from made alkaline with NazCOs and extracted with CHC13, and the DMF: yield 6.9 g (66%);mp 249-250’ dec. CHC13 removed i n L‘UCUO (rotary) to give a brownish yellow oil Acknowledgments. We thank Dr. M. D. Pittam and which was crystallized from EtOH: yield 7.8 g (45%);mp 63-64’, Compounds 2, 3, 5, 7, and 8 were prepared in a similar manner. Miss J . A. O’Brien for the biological results and Mr. G. MaCompound 2 was very soluble in EtOH and was isolated as the hyciak of the Lilly Research Laboratories, Indianapolis, Ind., drochloride salt. for the microanalytical data on the compounds described in 2-(4-N-n-Butylamidinostyryl)-5-nitro-l-vinylimidazole this paper. (14). The primary amide Id, 28.4 g (0.1 mol), was suspended in dry CHSC12 (300 ml) and stirred with a solution of Et30+BF4-, 20 g References (0.11 mol), in CH2C12 (30 ml) for 20 hr a t room temperature. The mixture was evaporated (rotary) to low volume and the solid (1) W. J. Ross, W. B. Jamieson, and M. C. McCowen, J . Med. stirred with anhydrous EtlO, filtered, washed with further EtzO, Chem., 16,347 (1973). (2)E. M. Lourie and W. Yorke, Ann. Trop. M e d . , 33,280 (1939). and dried in LWCUO. (3) H. King, E. M. Laurie, and W. Yorke, Lancet, 2,1360 (1937). This product, 25 g (0.062 mol), was added with stirring to liquid (4) W. A. Sexton “Chemical Constitution and Biological Activity,” ammonia (100 ml) and the excess ammonia allowed to evaporate 3rd ed, E & F.N. Spon, London, 1963, p 391. overnight. The greenish yellow solid was extracted with hot CHCb ( 5 ) R. F. Borch, Tetrahedron Lett., 61 (1968). and the CHC13 evaporated (rotary) to give the free imino ether: (6) H. .J. Barber and R. Slack, J . Amer. Chem. Soc., 66, 1607 yield 8.0 g (27%). Recrystallization from 2-propanol gave a highly (1944). crystalline solid: mp 178-179’. The recrystallized imino ether, 3 g (ca. 0.01 mol), was refluxed in ( 7 ) A. W. Dox, “Organic Syntheses,” Collect. Vol. I, Wiley, New MeOH (150 ml) with n-butylamine hydrochloride, 1.5 g (0.014 York, N.Y., 1941, p 5. mol), for 4 hr. The clear solution was cooled and the MeOH evapo(8) F. Hawking, E x p . Chemother., 1,129 (1963). (9) H. Meerwein, Org. Syn., 46,113 (1966). rated (rotary). The resultant solid was extracted with hot H20 12 Experimental Section
Cycloalkanones. 6. Separation of Hypocholesterolemic and Antifertility Activities in Derivatives of 2,8-Dibenzylcyclooctanone G. L. Carlson,*st I. H. Hall, and C. Piantadosi Department O/ Medicinat Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27514. Receiued October 3,1974 Fluoro and hydroxy derivatives of 2,8-dibenzylcyclooctanonewere prepared. Separation of antifertility activity from hypolipidemic and uterotropic effects was achieved with 2,8-bis(4-acetoxybenzyljcyclooctanone.Some enhancement of the hypolipidemic effect in relation to the uterotropic and antifertility activities was seen in 2,8-bis(4-fluorobenzyl jcyclooctanone. Synthetic methods for the hydroxy compounds are presented.
The hypocholesterolemic uterotropic, and antifertility activities of compounds related to the parent 2,8-dibenzylcyclooctanone (1) have been reported (Figure l ) . I s 2 An earlier study has shown that a causal relationship between uterotropic and hypolipidemic activities is ~ n l i k e l y ;how~ ever, the problem of separating the three activities remained. The changes in the effects of some derivatives [2,8-bis(4-methylbenzyl)cyclooctanone(2) and 2,8-bis(2methylbenzy1)cyclooctanone (3)] led to the speculation ‘This investigation was supported in part by a R. J. Reynolds Fellowship t o Gerald L. Carlson. We wish t o express our appreciation to Dr. Claude E. ‘I’eague. Jr., for his interest and encouragement.
that further modification of the aromatic nucleus could result in a separation of the antifertility activity from the hypolipidemic activity. Experimental Section 2,8-Bis(4-fluorobenzyl)cyclooctanone, 2,8-bis(4-methoxybenzyl)cyclooctanone, and 2,8-bis(4-methoxybenzyl)cyclooct a n o n e were prepared from the appropriate aldehydes using methods previously d e ~ c r i b e d . ~ 2,8-Bis(4-hydroxybenzyl)cyclooctanone (6).G e n e r a l Method f o r Aryl Methyl E t h e r Cleavage! NaH (4 g, 50%) in mineral oil was added to 75 ml of freshly distilled DMF at 5 O . Excess ethanethiol (7.5 ml) was added a t a rate sufficiently slow to prevent foaming over the top of the flask. 2,8-Bis(4-methoxybenzyl)cy-
